Inhibitors of fli1 and erg

Abstract

The invention relates to inhibitors of EWS-FLI1, pharmaceutical compositions containing the inhibitors, and methods of treating cancer, including Ewing sarcoma, leukemia, diffuse large B-cell lymphoma (DLBCL), and prostate cancer, comprising the administration of the inhibitors and pharmaceutical compositions thereof.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein:
 R is, for each of the available binding sites, independently selected from the group consisting of H, F, Cl, Br, I, CH 3 , OCH 3 , CF 3 , OCF 3 , NO 2 , NH 2 , OH, N(CH 3 ) 2 , CN, COCH 3 , CONH 2 , SO 2 CH 3 , and SO 2 NH 2 ; 
 m is an integer from 1 to 4; 
 W a , X a , and Y a  are for each occurrence independently O, CH 2 , NH, cycloalkyl, benzyl, heterocycloalkyl, or heteroaryl, and one or more of W a , X a , and Y a  are optionally not present, wherein the cycloalkyl, benzyl, heterocycloalkyl, and heteroaryl groups are independently unsubstituted or substituted, independently for each of the available binding sites, by H, F, Cl, Br, I, CH 3 , OCH 3 , CF 3 , OCF 3 , NO 2 , NH 2 , OH, N(CH 3 ) 2 , CN, COCH 3 , CONH 2 , SO 2 CH 3 , or SO 2 NH 2 ; 
 n a  is an integer from 0 to 10; 
 W b , X b , and Y b  are for each occurrence independently O, CH 2 , NH, cycloalkyl, benzyl, heterocycloalkyl, or heteroaryl, and one or more of W b , X b , and Y b  are optionally not present, wherein the cycloalkyl, benzyl, heterocycloalkyl, and heteroaryl groups are independently unsubstituted or substituted, independently for each of the available binding sites, by H, F, Cl, Br, I, CH 3 , OCH 3 , CF 3 , OCF 3 , NO 2 , NH 2 , OH, N(CH 3 ) 2 , CN, COCH 3 , CONH 2 , SO 2 CH 3 , or SO 2 NH 2 ; and 
 n b  is an integer from 0 to 10; 
 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The compound of  claim 1 , wherein n a  is an integer from 0 to 5. 
     
     
         3 . The compound of  claim 1 , wherein n a  is an integer from 0 to 3. 
     
     
         4 . The compound of  claim 1 , wherein n a  is 2. 
     
     
         5 . The compound of  claim 1 , wherein n a  is 1. 
     
     
         6 . The compound of  claim 1 , wherein n a  is 0. 
     
     
         7 . The compound of  claim 1 , wherein W a  and Y a  are each O and X a  is CH 2 . 
     
     
         8 . The compound of  claim 1 , wherein one of W a  and X a  is not present, the other of W a  and X a  is CH 2 , and Y a  is O. 
     
     
         9 . The compound of  claim 1 , wherein n b  is an integer from 0 to 3. 
     
     
         10 . The compound of  claim 1 , wherein n b  is 1. 
     
     
         11 . The compound of  claim 9 , wherein one of W b  and X b  is not present, the other of W b  and X b  is CH 2 , and Y b  is O. 
     
     
         12 . The compound of  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         13 . A pharmaceutical composition comprising a compound of  claim 1 , and a pharmaceutically acceptable excipient. 
     
     
         14 . A method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 1 . 
     
     
         15 . A method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition of  claim 13 . 
     
     
         16 . The method of  claim 14 , wherein the cancer is selected from the group consisting of Ewing sarcoma, leukemia, diffuse large B-cell lymphoma (DLBCL), and prostate cancer. 
     
     
         17 . The method of  claim 15 , wherein the cancer is selected from the group consisting of Ewing sarcoma, leukemia, diffuse large B-cell lymphoma (DLBCL), and prostate cancer. 
     
     
         18 . A process for preparing a compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein in formula (I):
 R is, for each of the available binding sites, independently selected from the group consisting of H, F, Cl, Br, I, CH 3 , OCH 3 , CF 3 , OCF 3 , NO 2 , NH 2 , OH, N(CH 3 ) 2 , CN, COCH 3 , CONH 2 , SO 2 CH 3 , and SO 2 NH 2 ; 
 m is an integer from 1 to 4; 
 W a , X a , and Y a  are for each occurrence independently O, CH 2 , NH, cycloalkyl, benzyl, heterocycloalkyl, or heteroaryl, and one or more of W a , X a , and Y a  are optionally not present, wherein the cycloalkyl, benzyl, heterocycloalkyl, and heteroaryl groups are independently unsubstituted or substituted, independently for each of the available binding sites, by H, F, Cl, Br, I, CH 3 , OCH 3 , CF 3 , OCF 3 , NO 2 , NH 2 , OH, N(CH 3 ) 2 , CN, COCH 3 , CONH 2 , SO 2 CH 3 , or SO 2 NH 2 ; 
 n a  is an integer from 0 to 10; 
 W b , X b , and Y b  are for each occurrence independently O, CH 2 , NH, cycloalkyl, benzyl, heterocycloalkyl, or heteroaryl, and one or more of W b , X b , and Y b  are optionally not present, wherein the cycloalkyl, benzyl, heterocycloalkyl, and heteroaryl groups are independently unsubstituted or substituted, independently for each of the available binding sites, by H, F, Cl, Br, I, CH 3 , OCH 3 , CF 3 , OCF 3 , NO 2 , NH 2 , OH, N(CH 3 ) 2 , CN, COCH 3 , CONH 2 , SO 2 CH 3 , or SO 2 NH 2 ; and 
 n b  is an integer from 0 to 10; 
 
         or a pharmaceutically acceptable salt thereof; 
         comprising:
 reacting a compound of formula (II) with a compound of formula (III) under conditions sufficient to form a compound of formula (IV): 
 
       
       
         
           
           
               
               
           
         
         reacting the compound of formula (IV) under conditions sufficient to form a compound of formula (V): 
       
       
         
           
           
               
               
           
         
         reacting the compound of formula (V) with a compound of formula (VI) under conditions sufficient to form the compound of formula (I): 
       
       
         
           
           
               
               
           
         
         wherein R, m, W a , X a , Y a , n a , W b , X b , Y b , and n b  in formulas (II), (Ill), (IV), (V), and (VI) are identical to how R, m, W a , X a , Y a , n a , W b , X b , Y b , and n b  are defined in formula (I). 
       
     
     
         19 . The process of  claim 18 , wherein the compound of formula (I) is selected from the group consisting of: